A multi-institutional team of researchers has discovered how a potential treatment strategy for Huntington’s disease (HD) produces its effects, verified its action in human cells and identified a previously unknown deficit in neural stem cells from patients with HD.
In their report, published in Proceedings of the National Academy of Sciences, the team describes finding how a group of compounds activates the NRF2 molecular pathway, which protects cells from several damaging influences, and also discovering that NRF2-mediated activity appears to be impaired in neural stem cells from the brains of HD patients.
A 2016 study by the same researchers identified a compound, which the investigators named MIND4, that appeared to protect against HD-associated neurodegeneration in two ways — by activating the NRF2-mediated pathway and by inhibiting the regulatory enzyme SIRT2, a strategy also being investigated to treat Parkinson’s disease. A related compound, called MIND4-17, was found to only activate the NRF2 pathway but to do so more powerfully than did MIND4. The current investigation’s overall goal was to examine whether the NRF2 activation responses observed in that study were also present in human cells, indicating their potential for therapeutic development.
The investigators found that MIND4-17 acts by mimicking the same process that activates the NRF2 pathway in response to oxidative stress. In stress-free conditions NRF2 is bound into a complex by two other proteins, one of which mediates a process leading to the breakdown of NRF2. MIND4-17 binds to and modifies the mediating protein in way that changes the shape and arrests formation of the protein complex, thereby allowing newly synthesized NRF2 to escape degradation and move to the nucleus where it can activate protective antioxidant genes.
NRF2 activation also induced anti-inflammatory effects in microglia and macrophages, immune cells known to infiltrate the brain in late-stage HD; and treatment with MIND4, which crosses the blood-brain barrier, reduced levels of a key inflammatory protein in a mouse model of HD.
In human neural stem cells from patients with HD — cells reflecting a range of the CAG nucleotide repeats found in the mutated gene that underlies the disorder — NRF2 activation in response to MIND4-17 was found to be reduced at levels correlating with the number of repeats.
Since MIND4-17 is unable to penetrate the blood brain barrier, future work is needed to develop powerful NRF2-activating compounds with enhanced brain permeability and to test their efficacy in models of HD and other neurodegenerative disorders.
Paper: “KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington’s disease patients”
Reprinted from materials provided by Massachusetts General Hospital